This Program Project will compare control of arteries and veins by the sympathetic nervous system (SNS), endothelin (ET-1), and superoxide anions in normotensive and hypertensive animals. A major goal is to determine if abnormalities in venous function contribute to the etiology of hypertension. Project 1 involves studies in rats instrumented to allow long-term recording of blood pressure, blood volume and mean circulatory filling pressure. This latter variable is an in vivo index of venoconstriction or venomotor tone. Most experiments will be in rats with DOCA-salt hypertension. In this model the SNS, ET-1 and superoxide anions all participate in hypertension development. We have produced in vivo evidence that the SNS, ET-1 and superoxide each increase venomotor tone in DOCA-salt hypertension, in vitro data from other projects in the Program have revealed important differences in control of veins by these factors in normotensive and DOCA-salt hypertensive rats. This information has been used to formulate four Specific Aims for Project 1. Specific Aim 1 is to determine if increased venomotor tone due to sympathetic venoconstriction, ET-1 and/or superoxide anions contributes to the development of DOCA-salt hypertension. Specific Aim 2 is to determine if increased venomotor tone due to sympathetic venoconstriction, ET-1 and/or superoxide anions help support established DOCA-salt hypertension by regulating cardiac output. Specific Aim3 will evaluate ET-1 levels and sympathetic activity in the splanchnic bed of DOCA-salt hypertensive rats. Specific Aim 4 capitalizes on our novel observation that chronic infusion of the selective ETB receptor agonist sarafotoxin 6c causes hypertension associated with increased venomotor tone and neurogenic pressor activity. Studies will characterize the role of ET receptor regulation, superoxide generation and sympathetic activity to veins in this new model of hypertension. This Project is unique in highlighting the veins and their role in vascular capacitance as an important component of the pathophysioiogy of hypertension. New findings here could suggest novel approaches to therapy of this important and prevalent disease. They also could provide insights into numerous other conditions involvinq venous dysfunction, including orthostatic disorders and heart failure.